Postmenopausal women experience a rapid loss of ovary function. The associated loss of estrogen often brings about heat sensation, hot flushes, sweating, and other vasomotor symptoms, which are major complaints of menopausal syndrome. The reduced secretion of the hormone is also considered to cause cardiovascular disorders and osteoporosis. In order to prevent or treat these symptoms, oral preparations and injections of estrogen are given to women suffering from menopausal syndrome. The oral administration, however, results in much of the drug being metabolized in the digestive tract and liver and thus requires a high dose to achieve the desired effect. The administration by injection not only accompanies pain caused by the needle, but also causes the blood estrogen level to increase rapidly. Moreover, the efficacy of the drug diminishes in a short period of time. When administered via these administration routes, estrogen may cause thrombosis, endometriosis, uterine cancer, and other side effects. For these reasons, it is necessary to find a way to maintain the drug level in the body at the minimum required level for an extended period of time.
One way to provide sustained drug release is via a transdermal absorption preparation. Since administration via this route is different from administration via digestive tract or liver and transdermal absorption preparations are easy to handle, this route of administration has drawn much attention and several attempts have been made to date to provide ideal transdermal absorption preparations.
One example is a reservoir-type preparation in which estradiol is dissolved in a gel made of hydroxypropyl cellulose and ethanol. This reservoir-type preparation controls the release of estradiol by the use of an ethylene-vinyl acetate film (Japanese Patent Laid-Open Publication No. Sho 57-154122). However, since these preparations contain a volatile ingredient, there is a fear that drug releasability is changed. In addition, contained ethanol is irritant to the skin, frequently causing rubor where the preparation is applied to the skin.
Another proposed example is a transdermal absorption preparation containing complex estrogen (Japanese Patent Laid-Open Publication No. Sho 60-152413). This preparation also contains menthol as a transdermal absorption enhancer. The problem of this preparation is that volatile menthol evaporates during storage or use, so that the rate of drug release changes over time.
Still another transdermal absorption preparation uses an acrylic adhesive in the adhesive layer (Japanese Patent Laid-Open Publications No. Hei 4-342532 and Hei 8-27003). The preparation contains as active components norethisterone, estradiol, and esters thereof. The acrylic adhesive used in this preparation has a low ability to release the drug and is irritant to the skin. The acrylic adhesive is thus unsuitable for transdermal absorption preparations for the purpose of continuous application over an extended period of time. Another estrogen-containing transdermal absorption patch using styrene-isoprene-styrene block copolymer (SIS) is proposed in which a fatty acid ester is used to serve as a component to dissolve estrogen (Japanese Patent Laid-Open Publications No. Hei 5-148145). The fatty acid ester used in this preparation not only decreases the cohesion of the adhesive, resulting in the adhesive remaining where it is applied, but is also irritant to the skin.
The skin tissue of a living body serves as a defense function to prevent the entrance of foreign substances into the living body. Thus, delivering effective doses of a drug through the skin is generally considered difficult. To overcome this problem, absorption enhancers are added to transdermal preparations. The addition of these enhancers in many cases increases the irritation to the skin, however.
The external preparation used in hormone replacement therapies must be left on the skin for a prolonged period of time to maintain the effective blood level of a drug. In order to allow the external preparation to be applied for a long period of time, it is necessary to improve the adhesive strength of a base material of the external preparation. In addition, it is particularly necessary to enhance the anchor effect of an adhesive on the irregularities of the skin surface in order to increase a holding power. To enhance the anchor effect of the adhesive on the irregularities of the skin surface, the activity of the polymer to serve as the adhesive base material must be increased. This, however, decreases the cohesive strength of the adhesive, which leads to occurrences of cohesive fractures and results in the adhesive remaining on the skin upon peeling-off of the external preparation. Thus, long-term application of the external preparation requires control over the anchor effect of the adhesive and its cohesive strength.
Many articles now suggest that the flexibility of a backing used in the external patches is a key factor in achieving high transdermal drug absorption. While such a flexible backing having physical properties adequate for such a purpose may be made of different materials such as low-density polymer films, nonwoven fabrics, and woven fabrics, each requires a substantial free volume to ensure the flexibility of the backing. However, a backing having a large free volume tends to adsorb much drug and, as a result, the rate of the drug release decreases after a long-term storage period, resulting in insufficient performance of the external patch.
In view of the aforementioned problems, it is an object of the present invention to provide an external patch that can ensure high transdermal absorption of estrogen and/or progestogen and have little irritancy to the skin.